Neopterin in a product produced by human monocyte-derived macrophages and dendritic cells and is produced in excess amount when neopterin derivatives are upon stimulation with interferon-γ (IFN-γ). In this process neopterin derivatives are able to interfere with reactive oxygen, chlorine and nitrogen species and neopterin itself contributes to oxidative stress. Higher level of neopterin levels and oxidative stress markers are reported in neuro-vascular complications associated with different disease conditions. In neurodegeneration process neopterin concentrations in serum and cerebro-spinal fluid is correlated with the cognitive decline in patients. A significant increase of neopterin concentrations with age is reported in earlier studies. A higher concentration of neopterin with neurodegenerative disorders is perhaps due to immune activation mainly in elderly population. The studies have further supported the view that increased neopterin concentrations are associated with oxidative stress which could underlie an increased demand of anti-oxidants in neurodegenerative conditions particularly in neurovascular complaints associated with diabetes where the oxidative stress play major role in their onset. An early identification of level of neopterin in diabetic patients with neuro-vascular complications is of clinical use as observations are made by various markers that higher neopterin concentrations were associated with reduced residual life span. A positive correlation has been established between neopterin concentration and type-2 diabetes mellitus. In neurodegenerative diseases, neopterin concentrations are correlated with serum concentrations of peroxides and homocysteine among patients with dementia. In such patients the serum concentration of peroxides and homocysteine is recorded among patients with dementia. In such patients the serum concentration of peroxides and neopterin were increased compared to normal people. Further, there is positive correlation between age and concentrations of peroxides, neopterin and homocysteine.
Interaction between neopterin and oxidative stress markers is reported by various markers. Promotion of oxidative stress is a fundamental principle of neopterin release in the process of vascular changes in hyperglycemic condition. Raised serum neopterin levels are found to be associated with severity of disease as well as mortality rate also.
Further, neopterin and TNF-α have also interdependencies, thus TNF-α has been described to enhance the effect of IFN-γ on neopterin synthesis in monocyte-derived macrophages. Neopterin levels are also increased in atherosclerosis in human. Thus application of estimation of neopterin in various diseases provides significant information for prevention and management of disease including neuro-vascular damage associated with diabetes.
Insulin resistance is a key feature of metabolic diseases and is defined as a state that requires more insulin to obtain the biological effects achieved by a lower amount of insulin in the normal state. Thus, any defects in the insulin signaling cascade can cause insulin resistance. Insulin stimulates a signaling network composed of a number of molecules, initiating the activation of insulin receptor tyrosine kinase and phosphorylation of the insulin receptor substrate (IRS) proteins (e.g., IRS-1 and IRS-2). Among several components of the network, the signaling axis of IRS proteins and PI3K, which activates downstream serine/threonine kinases including Akt, regulates most of the metabolic actions of insulin, such as suppression of hepatic glucose production and activation of glucose transport in muscle and adipocytes. It is known that this pathway is impaired at the multiple steps through alterations in the protein levels and activities of the signaling molecules, enzymes, and transcription factors in insulin resistance caused by obesity, a state of increased adiposity.
Risk factors for development of diabetic complications:
Impaired glucose tolerance (IGT) is significantly associated with a 6-10 fold increase in overall risk of progression to type-2 diabetes mellitus. Individuals with IGT have a greater frequency of cardiovascular risk factors like hypertension, dyslipidemia and obesity. Some of the common risk factors like greater duration of diabetes, hypertension, poor metabolic control, smoking, obesity and hyperlipidemia were more prone to develop diabetic complications. Type-2 diabetes mellitus increases the risk of adverse coronary events two-fold in men and four fold in women, due to presence of CHD risk factors.
Further, altered homocysteine, neopterin, leptin, inflammatory bio-markers all are significantly associated with neuro-vascular complications among diabetic patients. The major cardiovascular risk factors affects the endothelium, promoting enhanced endothelial permeability, expression of inflammatory markers and upregulation of particular enzymes that produce oxygen-free radicals, which together lead to the development of a low-grade chronic inflammatory state in the arterial wall. This type of action is responsible for various vascular complications in type-2 diabetes mellitus. Similarly elevated levels of circulating inflammatory markers among type-2 diabetes mellitus are responsible for development of cognitive impairment including development of vascular disease.
Various studies have demonstrated clear benefits of good glycemic control in preventing or retarding the vascular complications in diabetic patients.
Recently, a number of anti-diabetic agents are available to control hyperglycemia but due to long-term/life-long consumption, their use is restricted because of the risk profile. However, no suitable remedial measure is available having activity in prevention and management of neurogenic vascular complications among diabetic patients which badly hampers the quality as well as span of life. The available anti-hyperglycemic drugs include insulin secretagogues (sulfonylureas or meglitinides), insulin sensitizers (metformin or thiazolidinediones) and inhibitors of carbohydrate absorption (a-glucosidase inhibitors) but their long term application causes gastrointestinal disturbances, renal and hepatic impairments, etc. Therefore, there is an urgent need of satisfactory therapeutic modalities free from side-effects. In Ayurveda, various pharmacologic and non-pharmacologic methods have been prescribed for the prevention and management of diabetes and associated complications. Under the scheme Ayurveda as well as other traditional systems of medicine several plant-based drugs have been advocated to manage hyperglycemia.
Taking the lead from Ayurveda, a plant based formulation containing hydro-alcoholic extract of Berberis aristata, Trigonella foenum-graecum and Salecia parvillora in an effective doses determined by us in pre-clinical analysis have been developed and validated for its neopterin lowering property with the object to prevention and treatment of neuro-vascular complications among type-2 diabetes patients. The out come of this study has novelty, innovative and has acceptability for general population as earlier no such type of study is carried out.